The long term goals of the proposal are to determine the extent to which modulation of the local injury site, combined with trophic factor support and neural tissue transplantation can lead to structural repair of the chronically injured spinal cord.
The specific aims address the hypothesis that combinations of experimental interventions in the chronic state after injury can promote axonal regeneration and integration across an injury site. It will also be determined whether progressive changes in chronically injured neurons influence their ability to respond to these interventive approaches and whether non-neuronal cells associated with the injury site modulate the neuronal response to injury and to trophic factor treatment.
Aim I will utilize an established SCI-peripheral nerve graft model to determine how treatments of the graft spinal cord interface with compounds that modulate the non-neuronal cell response to injury can effectively promote axonal growth beyond the PN graft, into the dorsal horn of the spinal cord.
The second aim will determine if a combination of neurotrophic factors and fetal tissue transplantation can increase axonal growth from a PN graft, into the spinal cord. Experiments for Aim III will determine why the regenerative effort of some neurons at different post injury intervals appears to be greater than that exhibited by other neurons. Neuronal survival, axonal retraction and changes in the expression of regeneration associated genes at various stages after spinal cord injury and in response to trophic factor treatment will be measured in relation to the regenerative response of specific brainstem neuron populations.
In aim I V, changes in the cellular and biochemical composition of nonneuronal cells at a chronic lesion site and after trophic factor treatment will be examined by immunocytochemical labeling and multiprobe ribonuclease protection assays. We will compare these changes with the regenerative effort of factor-treated neurons observed in the previous Aims to reach and understanding of the impact of non-neuronal cell responses on the ability to promote regeneration. Overall, these experiments will provide valuable information about cellular and molecular aspects of the neuronal and non-neuronal response to long term injury and will assist in the design of interventive therapies to repair the chronically injured spinal cord.
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